Multi-scale modeling of GMP di_erentiation based on single-cell genealogies.

MedLine Citation:

PMID:
22708849
Owner:
NLM
Status:
Publisher

Abstract/OtherAbstract:

Hematopoiesis is often pictured as a hierarchy of branching decisions, giving rise to all mature blood cell types from the stepwise di_erentiation of a single cell, the hematopietic stem cell. Different aspects of this process have been modeled with different experimental and theoretical techniques, and on a spectrum of scales. In this contribution, we integrate the more common population-based approach with a single-cell- resolved molecular differentiation model to study the possibility to infer mechanistic knowledge of the differentiation process. We focus on a submodule of hematopoiesis, the diffrentiation of granulocyte- monocyte progenitors (GMPs) to granulocytes or monocytes. Within a branching process model, we infer the differention probability of GMPs from experimentally quanti_ed heterogeneity of colony assays under permissive conditions, where both granulocytes and monocytes can emerge. We compare the predictions with the diffrentiation probability in genealogies determined from single-cell time-lapse microscopy. Contrary to the branching process model, we _nd the differentiation probability as determined by differentiation marker onset to rise with the generation of the cell within the genealogy. To study this feature from a molecular perspective, we set up a stochastic toggle switch model, where we execute the intrinsic lineage decision with two antagonistic transcription factors. We _nd parameter regimes that allow for both time-dependent and time-independent di_erentiation probabilities. Finally, we infer parameters for which the model matches experimentally observed differentiation probabilities via Approximate Bayesian Computing. These parameters suggest different timescales in the dynamics of granulocyte and monocyte diffrentiation. We provide a multi-scale picture of cell differentiation in murine GMPs and illustrates the need for single-cell time-resolved observations of cellular decisions.